Background: The objective of this Phase I/II trial was to determine the response rate and overall survival (OS) of concurrent chemoradiotherapy (CT-RT) in combination with the radiosensitizer Nelfinavir in locally advanced non-small cell lung cancer (LA-NSCLC) compared to historical controls. Methods: Nelfinavir (Dose Level (DL) 1: 625mg PO BID, DL2:1250mg PO BID) was administered for 7 to 14 days prior to and during concurrent CT-RT to patients (pts) with biopsy confirmed unresectable IIIA and IIIB NSCLC. 23 pts (65.7%) had stage IIIA disease; 11 pts (31.4%) had stage IIIB disease; 1 pt (2.9%) had N2 recurrence after surgery. Median age was 60 years for all pts. 19 pts (54.2%) were male, 16 (45.7%) were female. Patients were treated with concurrent CT-RT to a dose of 66.6/1.8Gy and cisplatinum and VP-16. DLTs were defined as any treatment related Grade 4 hematologic toxicity requiring a break in therapy or non-hematologic Grade ≥ 3 toxicity except esophagitis and pneumonitis. Protocol specified criteria for compliance included receiving greater than 80% of the prescribed RT treatments and 70% of the prescribed Nelfinavir doses. Results: Thirty-five pts were enrolled and met protocol-specified criteria for compliance, 5 at DL1 and 30 at DL2. No DLTs were observed. The recommended phase II dose of Nelfinavir was 1250 mg PO BID. Median follow-up for all pts was 6.8 years and minimum follow-up for survivors was 5 years. 33 of the 35 pts had evaluable post-treatment CT with RECIST response rate of 94% and (31/33) stable disease rate of 6% (2/33). The cumulative incidence of local failure as site of first failure was 20%, with the median time to failure not reached (NR). The cumulative incidence of distant failure as site of first failure was 51%, with the median time to distant failure of 15.8 months. The median progression-free survival was 12 months. The median OS for all pts was 40 months; 5 year OS was 37 %. Conclusions: Nelfinavir administered with concurrent CT-RT is associated with acceptable toxicity and very promising local control, overall response rate, and survival in unresectable LA-NSCLC. These data suggest that Nelfinavir may enhance the efficacy of chemo-RT in this disease. Clinical trial information: NCT00589056